chr18-2694694-G-A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_015295.3(SMCHD1):​c.1040+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SMCHD1
NM_015295.3 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 8.90

Publications

2 publications found
Variant links:
Genes affected
SMCHD1 (HGNC:29090): (structural maintenance of chromosomes flexible hinge domain containing 1) This gene encodes a protein which contains a hinge region domain found in members of the SMC (structural maintenance of chromosomes) protein family. [provided by RefSeq, Dec 2011]
SMCHD1 Gene-Disease associations (from GenCC):
  • arhinia, choanal atresia, and microphthalmia
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics, ClinGen, Illumina
  • facioscapulohumeral muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hyposmia-nasal and ocular hypoplasia-hypogonadotropic hypogonadism syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 18-2694694-G-A is Pathogenic according to our data. Variant chr18-2694694-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 464158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SMCHD1NM_015295.3 linkc.1040+1G>A splice_donor_variant, intron_variant Intron 8 of 47 ENST00000320876.11 NP_056110.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SMCHD1ENST00000320876.11 linkc.1040+1G>A splice_donor_variant, intron_variant Intron 8 of 47 5 NM_015295.3 ENSP00000326603.7 A6NHR9-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1457004
Hom.:
0
Cov.:
30
AF XY:
0.00000414
AC XY:
3
AN XY:
724856
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33144
American (AMR)
AF:
0.00
AC:
0
AN:
43242
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25988
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39606
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85378
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53376
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5724
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1110348
Other (OTH)
AF:
0.00
AC:
0
AN:
60198
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.405
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74316
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41418
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Facioscapulohumeral muscular dystrophy 2 Pathogenic:1
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change affects a donor splice site in intron 8 of the SMCHD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMCHD1 are known to be pathogenic (PMID: 23143600). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with facioscapulohumeral-like muscular dystrophy (PMID: 24755953). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 464158). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
Sep 28, 2022
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (Winston et al. 2015); This variant is associated with the following publications: (PMID: 24755953, Hiramuki2022[Preprint]) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
8.9
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.42
Position offset: 3
DS_DL_spliceai
1.0
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1245372794; hg19: chr18-2694692; COSMIC: COSV99861003; API